Neurological disorders are increasing in incidence and prevalence worldwide, and as such therapies are in imminent need. However, neurological disorders are phenotypically heterogeneous, both in familial and sporadic forms, and often have an unknown etiology. Thus targeting a single pathological mechanism, is less likely to provide disease modification with a significant clinical benefit, unless the nature of the pathological mechanism is the key “driver” of the disease.
Several mechanisms and pathways have been implicated in neurological disorders such as neurological diseases, including accumulation of neurotoxic substances, inflammation, lipid metabolism, oxidative stress, autophagy, protein degradation and mitochondrial dysfunction. However, it remains unclear whether they are the cause of the disease or the consequence of the primary and/or secondary damage. Consequently, therapies based on some of these individual mechanisms have not been clinically successful. Many efforts to develop disease-modifying therapies for neurological diseases have followed a toxin-reducing approach given that accumulation of misfolded toxic proteins in the brain is considered to be a key pathogenic factor for some neurodegenerative diseases. However, clinical success by lowering toxic proteins has been limited, such as Aβ in Alzheimer's Disease, although recent trials in patients with mild disease show encouraging results.
Targeting pathogenesis (the biological mechanism(s) that lead to the diseased state) may be a suitable approach for prophylactic or preventative treatment; however, targeting pathophysiology (the endogenous biological mechanisms operating within the diseased state) may be a better approach for therapeutic intervention in a neurological disorder that is already present.
It is possible to use this alternative pathophysiological therapeutic approach by targeting the endogenous neurotrophic and neuroprotective pathways that play a role in neuronal survival, function, plasticity, and homeostasis. There is evidence indicating that endogenous mechanisms can be significantly down regulated in neurological disorders.
Neurotrophins are endogenous growth factors that regulate the development, maintenance and functions of the central and peripheral nervous systems (CNS and PNS respectively). The Nerve Growth Factor (NGF) family of ligands primarily signal through a high-affinity Trk receptor [TrkA for NGF, TrkB for BDNF (Brain Derived Neurotrophic Factor) and NT-4 (Neurotrophin 4, NT-4/5), TrkC for NT-3 (Neurotrophin 3)] and also by binding to the low-affinity pan-neurotrophin receptor, p75NTR. Signal transduction through Trk receptors usually enhance cell survival, whereas signalling of neurotrophins through p75NTR, in absence of Trk receptors, in general, facilitate apoptosis.
There is preclinical evidence supporting the role of the BDNF-TrkB pathway in promoting the survival and function of CNS neurons both in vitro and in vivo. Further, four clinical trials using BDNF have been conducted in ALS. In addition, a phase I, double-blind, placebo-controlled single ascending dose study in healthy volunteers with subcutaneous injection of a TrkB agonist antibody (Clinical Trial NCT01262690, sponsor: Pfizer) was terminated due to the emergent safety concern of sensory symptoms (no study results were published).
In summary, there remains a need for treatment of neurological disorders and other disorders where restoring or enhancing the BDNF-TrkB pathway by activating TrkB can be beneficial.